Alzheimer's Disease (AD) is an age-related disorder that causes a dramatic loss of cognitive function and affects millions of elderly individuals worldwide. It is characterized pathologically by the presence of protein aggregates of beta amyloid (AB) and tau and a progressive neurodegeneration. There is exceedingly strong evidence that abnormal assemblies of AB are neurotoxic and have a key role in AD. Why AB accumulates or induces neurodegeneration is unclear. Following up on a report that linked Beclin 1, an essential protein involved in the early steps of autophagy, to neurodegeneration and cell death in the lurcher mouse we decided to explore the possibility that Beclin 1 and autophagy may have a role in AD. Autophagy is the major pathway involved in the degradation of long-lived proteins and organelles, cellular remodeling, and survival during nutrient starvation. It is unclear whether autophagy exerts a pathological or protective role in neurodegeneration and Alzheimer's Disease. We discovered that expression of Beclin 1 is reduced more than 50% in gray matter of the frontal cortex in postmortem brains from AD cases compared with age-matched cases of Lewy body variant of AD, Huntington's disease, Parkinson's disease, or nondemented controls. This decrease was not simply due to a loss of neurons since levels of the neuronal protein neuron specific enolase were not altered. We found that genetic reduction of Beclin 1 expression in beclin 1-/+ haploinsufficient mice results in less autophagy in primary neurons and is associated with neurodegeneration in 9-month-old mice. Beclin 1 deficiency in APP transgenic mice, a model for AD, results in increased accumulation of fragments of APP and AB in cells and in the extracellular space and was associated with increased inflammation. In addition, increased autophagy in cultured neuroblastoma cells reduces APP fragments while siRNA mediated reduction in Beclin 1 expression increases APP fragments and AB. Together, these studies provide strong evidence for a role of Beclin 1 and autophagy in AD pathogenesis and they open a new pathway to potentially target this disease. The goal of this application is to determine how Beclin 1 is regulated in neurons and in mouse brains, how it affects the production and turnover of AB and its precursors, and whether increased production of Beclin 1 may be protective and ameliorate neurodegeneration and AD-like disease in mice. We also expect to establish that Beclin 1 is a major modifier of AD pathogenesis and that increasing Beclin 1 levels reduces disease. If successful, our findings may provide new targets for the treatment of AD and neurodegeneration.